The present invention relates to polymorphs of brimonidine pamoate, compositions comprising such polymorphs, and methods of treating or controlling diseases using such polymorphs. In particular, the present invention relates to stable polymorphs of brimonidine pamoate and such compositions comprising such polymorphs for sustained release thereof.
Polymorphism is a property of a substance to exist in more than one solid state crystal structures. The various polymorphic forms—polymorphs—of a crystal have different crystal lattices and, thereby, different physical and chemical properties, such as density, hardness, chemical stability, solubility, rate of dissolution in different solvents, melting point, phase transformation, hygroscopicity, interactions with biological systems, etc. In addition, the term “pseudopolymorphisms” has been applied to different hydrates and solvates of a crystalline material in which water or solvent molecules have been built into the crystal lattice.
Brimonidine, 5-bromo-6-(2-imidazolidinylideneamino)quinoxaline (Formula I), is an α2 selective adrenergic receptor agonist that has been used in the treatment of open-angle glaucoma by decreasing aqueous humor production and increasing uveoscleral outflow.

For this use, topical ophthalmic solutions have been formulated and the tartrate salt of brimonidine has been used to provide increased solubility of brimonidine. The solubility of brimonidine tartrate is 34 mg/mL in water, and 2.4 mg/mL in a pH 7.0 phosphate buffer while the solubility of brimonidine freebase is negligible in water (see; e.g., U.S. Patent Application Publication 2006/0257452).
Recent studies suggested that brimonidine eye drops may have a neuroprotective effect in a rodent model of ischemic-induced optic nerve cell death. N. O. Danylkova et al., Exp. Eye Res., Vol. 84, 293 (2007); M. P. Lafuente et al., Exp. Eye Res., Vol. 74, 1981 (2002). However, topical application of brimonidine may not be the most effective manner to provide therapeutic effect to neurological tissues in the back of the eye because of the rapid clearance of topically applied compositions.
Intravitreal delivery of brimonidine can provide better access of the drug to the tissues in the back of the eye. Such delivery can be achieved by injecting a liquid-containing composition into the vitreous, or by placing polymeric drug delivery systems, such as implants and microparticles, into the vitreous. Examples of biocompatible implants for placement in the eye have been disclosed in a number of patents, such as U.S. Pat. Nos. 4,521,210; 4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242; 5,824,072; 5,869,079; 6,074,661; 6,331,313; 6,369,116; and 6,699,493. However, intravitreal administration of drugs should be as infrequent as possible to avoid unnecessary disturbance of the eye.
Therefore, it is very desirable to provide stable brimonidine salts for the preparation of sustained-release compositions. It is also very desirable to provide brimonidine salts that are stable in the vitreous humor. In addition, it is also very desirable to provide such brimonidine salts for duration in ocular environments where they can provide effective neuroprotection to the optic nerve system.